Self-reported non-adherence to antiretroviral therapy repeatedly assessed by two questions predicts treatment failure in virologically suppressed patients.

BACKGROUND: The aim of this study was to explore the predictive value of longitudinal self-reported adherence data on viral rebound. METHODS: Individuals in the Swiss HIV Cohort Study on combined antiretroviral therapy (cART) with RNA <50 copies/ml over the previous 3 months and who were interviewed about adherence at least once prior to 1 March 2007 were eligible. Adherence was defined in terms of missed doses of cART (0, 1, 2 or >2) in the previous 28 days. Viral rebound was defined as RNA >500 copies/ml. Cox regression models with time-independent and -dependent covariates were used to evaluate time to viral rebound. RESULTS: A total of 2,664 individuals and 15,530 visits were included. Across all visits, missing doses were reported as follows: 1 dose 14.7%, 2 doses 5.1%, >2 doses 3.8% taking <95% of doses 4.5% and missing > or =2 consecutive doses 3.2%. In total, 308 (11.6%) patients experienced viral rebound. After controlling for confounding variables, self-reported non-adherence remained significantly associated with the rate of occurrence of viral rebound (compared with zero missed doses: 1 dose, hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.72-1.48; 2 doses, HR 2.17, 95% CI 1.46-3.25; >2 doses, HR 3.66, 95% CI 2.50-5.34). Several variables significantly associated with an increased risk of viral rebound irrespective of adherence were identified: being on a protease inhibitor or triple nucleoside regimen (compared with a non-nucleoside reverse transcriptase inhibitor), >5 previous cART regimens, seeing a less-experienced physician, taking co-medication, and a shorter time virally suppressed. CONCLUSIONS: A simple self-report adherence questionnaire repeatedly administered provides a sensitive measure of non-adherence that predicts viral rebound.

Schizotypy and hemispheric asymmetry: results from two Chapman scales, the O-LIFE questionnaire, and two laterality measures

Schizotypy is a multidimensional personality construct representing the extension of psychosis-like traits into the general population. Schizotypy has been associated with attenuated expressions of many of the same neuropsychological abnormalities as schizophrenia, including atypical pattern of functional hemispheric asymmetry. Unfortunately, the previous literature on links between schizotypy and hemispheric asymmetry is inconsistent with some research indicating that elevated schizotypy is associated with relative right over left hemisphere shifts, left over right hemisphere shifts, bilateral impairments, or with no hemispheric differences at all. This inconsistency may result from different methodologies, scales, and / or sex proportions between studies. In a within-participant design, we tested for the four possible links between laterality and schizotypy by comparing the relationship between two common self-report measures of multidimensional schizotypy (the O-LIFE questionnaire, and two Chapman scales, magical ideation and physical anhedonia) and performance in two computerized lateralised hemifield paradigms (lexical decision, chimeric face processing) in 80 men and 79 women. Results for the two scales and two tasks did not unequivocally support any of the four possible links. We discuss the possibilities that a link between schizotypy and laterality 1) exists, but is subtle, probably fluctuating, unable to be assessed by traditional methodologies used here; 2) does not exist, or 3) is indirect, mediated by other factors (e.g. stress-responsiveness, handedness, drug use) whose influences need further exploration.

Association of work related chronic stressors and psychiatric symptoms in a Swiss sample of police officers : a cross sectional questionnaire study

Purpose (1) To identify work related stressors that are associated with psychiatric symptoms in a Swiss sample of policemen and (2) to develop a model for identifying officers at risk for developing mental health problems. Method The study design is cross sectional. A total of 354 male police officers answered a questionnaire assessing a wide spectrum of work related stressors. Psychiatric symptoms were assessed using the "TST questionnaire" (Langner in J Health Hum Behav 4, 269-276, 1962). Logistic regression with backward procedure was used to identify a set of variables collectively associated with high scores for psychiatric symptoms. Results A total of 42 (11.9%) officers had a high score for psychiatric symptoms. Nearly all potential stressors considered were significantly associated (at P < 0.05) with a high score for psychiatric symptoms. A significant model including 6 independent variables was identified: lack of support from superior and organization OR = 3.58 (1.58-8.13), self perception of bad quality work OR = 2.99 (1.35-6.59), inadequate work schedule OR = 2.84 (1.22-6.62), high mental/intellectual demand OR = 2.56 (1.12-5.86), age (in decades) OR = 1.82 (1.21-2.73), and score for physical environment complaints OR = 1.30 (1.03-1.64). Conclusions Most of work stressors considered are associated with psychiatric symptoms. Prevention should target the most frequent stressors with high association to symptoms. Complaints of police officers about stressors should receive proper consideration by the management of public administration. Such complaints might be the expression of psychiatric caseness requiring medical assistance. Particular attention should be given to police officers complaining about many stressors identified in this study's multiple model. [Authors]

Subjective mental time: the functional architecture of projecting the self to past and future.

Abstract Human experience takes place in the line of mental time (MT) created through 'self-projection' of oneself to different time-points in the past or future. Here we manipulated self-projection in MT not only with respect to one's life events but also with respect to one's faces from different past and future time-points. Behavioural and event-related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time-points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re-experienced or pre-experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo-parietal and insular cortices. These behavioural and neural data suggest that self-projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie OSHO-53 phase II study.

Background We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. Patients and methods From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. Results Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. Conclusions Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

Clinical effectiveness of direct class II restorations: a meta-analysis.

Purpose: More than five hundred million direct dental restorations are placed each year worldwide. In about 55% of the cases, resin composites or compomers are used, and in 45% amalgam. The longevity of posterior resin restorations is well documented. However, data on resin composites that are placed without enamel/dentin conditioning and resin composites placed with self-etching adhesive systems are missing. Material and Methods: The database SCOPUS was searched for clinical trials on posterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimum number of restorations at last recall = 20; (3) report on dropout rate; (4) report of operative technique and materials used; (5) utilization of Ryge or modified Ryge evaluation criteria. For amalgam, only those studies were included that directly compared composite resin restorations with amalgam. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. P-values under 0.05 were considered significant. Results: Of the 373 clinical trials, 59 studies met the inclusion criteria. In 70% of the studies, Class II and Class I restorations had been placed. The overall success rate of composite resin restorations was about 90% after 10 years, which was not different from that of amalgam. Restorations with compomers had a significantly lower longevity. The main reason for replacement were bulk fractures and caries adjacent to restorations. Both of these incidents were infrequent in most studies and accounted only for about 6% of all replaced restorations after 10 years. Restorations with macrofilled composites and compomer suffered significantly more loss of anatomical form than restorations with other types of material. Restorations that were placed without enamel acid etching and a dentin bonding agent showed significantly more marginal staining and detectable margins compared to those restorations placed using the enamel-etch or etch-and-rinse technique; restorations with self-etching systems were between the other groups. Restorations with compomer suffered significantly more chippings (repairable fracture) than restorations with other materials, which did not statistically differ among each other. Restorations that were placed with a rubber-dam showed significantly fewer material fractures that needed replacement, and this also had a significant effect on the overall longevity. Conclusion: Restorations with hybrid and microfilled composites that were placed with the enamel-etching technique and rubber-dam showed the best overall performance; the longevity of these restorations was similar to amalgam restorations. Compomer restorations, restorations placed with macrofilled composites, and resin restorations with no-etching or self-etching adhesives demonstrated significant shortcomings and shorter longevity.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): Validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Immunology of viral disease, how to curb persistent infection

1. 1. Summaries 1.1. Preamble and extended abstract The present thesis dissertation addresses the question of antiviral immunity from the particular standpoint of the adaptive T cell-mediated immune response. The experimental work is presented in the form of three published articles (two experimental articles and one review article, see sections 4.1, 4.2 and 4.3 on pages 73, 81 and 91, respectively), describing advances both in our understanding of viral control by CD8 T lymphocytes, and in vaccine development against the Human Immunodeficiency Virus Type 1 (HIV-1). Because the articles focus on rather specialized areas of antiviral immunity, the article sections are preceded by a general introduction (section 3) on the immune system in general, and on four viruses that were addressed in the experimental work, namely HIV-1, Cytomegalovirus (CMV), Epstein Barr Virus (EBV) and Influenzavirus (Flu). This introduction section is aimed at providing a glimpse on viral molecular biology and immunity, to help the hypothetical non-expert reader proceeding into the experimental part. For this reason, each section is presented as individual entity and can be consulted separately. The four viruses described are of peculiar relevance to immunity because they induce an array of opposite host responses. Flu causes a self limiting disease after which the virus is eradicated. CMV and EBV cause pauci-symptomatic or asymptomatic diseases after which the viruses establish lifelong latency in the host cells, but are kept in check by immunity. Eventually, HIV-1 establishes both latency - by inserting its genome into the host cell chromosome - and proceeds in destroying the immune system in a poorly controlled fashion. Hence, understanding the fundamental differences between these kinds of viral host interactions might help develop new strategies to curb progressive diseases caused by viruses such as HIV-1. Publication #1: The first article (section 4.1, page 73) represents the main frame of my laboratory work. It analyses the ability of CD8 T lymphocytes recovered from viral-infected patients to secrete interferon γ (IFN-γ) alone or in conjunction with interleukin 2 (IL-2) when exposed in vitro to their cognate viral antigens. CD8 T cells are instrumental in controlling viral infection. They can identify infected cells by detecting viral antigens presented at the surface of the infected cells, and eliminate both the cell and its infecting virus by triggering apoptosis and/or lysis of the infected cell. Recognition of these antigens triggers the cognate CD8 cells to produce cytokines, including IFN-γ and IL-2, which in turn attract and activate other pro-inflammatory cells. IFN-γ triggers both intrinsic antiviral activity of the infected cells and distant activation of pro-inflammatory cells, which are important for the eradication of infection. IL-2 is essential for clonal expansion of the antigen (Ag)-specific CD8 T cell. Hence the existence of Ag-specific CD8 cells secreting both IFN-γand IL-2 should be beneficial for controlling infection. In this first work we determined the percentage of IFN-y/IL-2 double positive and single IFN-γsecreting CD8 T cells against antigens HIV-1, CMV, EBV and Flu in three groups of subjects: (i) HIV-1 infected patients progressing to disease (progressors), (ii) HIV-1-infected subjects not progressing to disease (long-term non progressors or LTNP), and (iii) HIV negative blood donors. The results disclosed a specific IFN-y/IL-2 double positive CD8 response in all subjects able to control infection. In other words, IFN-y/IL-2 double positive CD8 cells were present in virus-specific CD8 T cells against Flu, CMV and EBV as well against HIV-1 in LTNP. In contrast, progressors only had single IFN-γsecreting CD8 T cells. Hence, the ability to develop an IFN-y/IL-2 double positive response might be critical to control infection, independently of the nature of the virus. Additional experiments helped identify the developmental stage of the missing cells (using different markers such as CD45RA and CCR7) and showed a correlation between the absence of IL-2 secreting CD8 T cells and a failure in the proliferation capacity of virus-specific CD8 T cells. Addition of exogenous IL-2 could restore clonal expansion of HIV-1 specific CD8 T cells, at least in vitro. It could further been shown, that IL-2 secreting CD8 T cells are sufficient to support proliferation even in absence of CD4 help. However, the reason for the missing IFN-y/IL-2 double positive CD8 T cell response in HIV-1 progessors has yet to be determined. Publication #2: The second article (section 4.2, page 81) explores new strategies to trigger CD8 T cell immunity against specific HIV-1 proteins believed to be processed and exposed as "infection signal" at the surface of infected cells. Such signals consist of peptide fragments (8- 13 amino acids) originating from viral proteins and presented to CD8 T cells in the frame of particular cell surface molecules of the major histocompatibility complex class I* (MHC I). To mimic "natural" viral infection, the HIV-1 polyprotein Gagpolnef was inserted and expressed in either of two attenuated viruses i.e. vaccinia virus (MVA) or poxvirus (NYVAC). Mice were infected with these recombinant viruses and specific CD8 T cell response to Gagpolnef peptides was sought. Mice could indeed mount a CD8 T cell response against the HIV-1 antigens, indicating that the system worked, at least in this animal model. To further test whether peptides from Gagpolnef could also be presented in the frame of the human MHC class I proteins, a second round of experiments was performed in "humanized" transgenic mice expressing human MHC molecules. The transgenic mice were also able to load Gagpolnef peptides on their human MHC molecule, and these cells could be detected and destroyed by Ag-specific CD8 T cells isolated from HIV-1-infected patients. Therefore, expressing Gagpolnef on attenuated recombinant viruses might represent a valid strategy for anti-HIV-1 immunization in human. Publication #3: This is a review paper (section 4.3, page 91) describing the immune response to CMV and newly developed methods to detect this cellular immune response. Some of it focuses on the detection of T cells by using in vitro manufactured tetramers. These consist of four MHC class I molecules linked together and loaded with the appropriate antigenic peptide. The tetramer can be labeled with a fluorochrome and analyzed with a fluorescence-activated cell sorter. Taken together, the work presented indicates that (i) an appropriate CD8 T cell response consisting of IFN-y/IL-2 double positive effectors, can potentially control viral infection, including HIV-1 infection, (ii) such a response might be triggered by recombinant viral vaccines, and (iii) CD8 T cell response can be monitored by a variety of techniques, including recently-developed MHC class I tetramers. 1. 2. Préambule et résumé élargi Le présent travail de thèse s'intéresse à l'immunité antivirale du point de vue particulier de la réponse adaptative des cellules T. Le travail expérimental est présenté sous la forme de trois articles publiés (2 articles expérimentaux et 1 article de revue, voir sections 4.1, 4.2 et 4.3, pages 58, 66 et 77, respectivement), décrivant des progrès dans la compréhension du contrôle de l'infection virale par les lymphocytes T CD8, ainsi que dans le développement de nouveaux vaccins contre le Virus d'Immunodéficience de Humaine de type 1 (VIH-1). En raison du caractère spécialisé de l'immunité antivirale de type cellulaire, les articles sont précédés par une introduction générale (section 3), dont le but est de pourvoir le lecteur non avisé avec des bases nécessaire à une meilleure appréhension du travail expérimental. Cette introduction présente les grandes lignes du système immunitaire, et décrit de façon générale les 4 virus utilisés dans le travail expérimental: à savoir le virus VIH-1, le Cytomégalovirus (CMV), le virus Epstein Barr (EBV) et le virus Influenza A (Flu). Toutes les sections sont présentées de façon individuelle et peuvent être consultées séparément. La description des 4 virus a une pertinence particulière quant à leur interaction avec le système immun. En effet, ils induisent une panoplie de réponses immunitaires s'étendant aux extrêmes de la réaction de l'hôte. Influenza A est à l'origine d'une maladie cytopathique aiguë, au décours de laquelle le virus est éradiqué par l'hôte. CMV et EBV sont classiquement à l'origine d'infections pauci-symptomatiques, voire asymptomatiques, après lesquelles les virus persistent de façon latente dans la cellule hôte. Cependant, ils restent sous le contrôle du système immun, qui peut prévenir une éventuelle réactivation. Enfin, VIH-1 s'établit à la fois en infection latente - par l'insertion de son génome dans le chromosome des cellules hôtes - et en infection productive et cytopathique, échappant au contrôle immunitaire et détruisant ses cellules cibles. La compréhension des différences fondamentales entre ces différents types d'interactions virus-hôte devraient faciliter le développement de nouvelles stratégies antivirales. Article 1: Le premier article (section 4.1 Page 58) représente l'objet principal de mon travail de laboratoire. Il analyse la capacité des lymphocytes T CD8 spécifiques de différent virus à sécréter de l'interféron gamma (IFN-y) et/ou de l'interleukine 2 (IL-2) après stimulation par leur antigène spécifique. Les cellules T CD8 jouent un rôle crucial dans le contrôle des infections virales. Elles identifient les cellules infectées en détectant des antigènes viraux présentés à la surface de ces mêmes cellules, et éliminent à la fois les cellules infectées et les virus qu'elles contiennent en induisant l'apoptose et/ou la lyse des cellules cibles. Parallèlement, l'identification de l'antigène par la cellule T CD8 la stimule à sécréter des cytokines. L'IFN-γen est un exemple. L'IFN-γ stimule les cellules infectées à développer une activé antivirale intrinsèque. De plus, il attire sur place d'autres cellules de l'inflammation, et active leur fonction d'éradication des pathogènes. L'IL-2 est un autre exemple. L'IL-2 est essentielle à l'expansion clonale des cellules T CD8 spécifiques à un virus donné. Elle est donc essentielle à augmenter le pool de lymphocytes antiviraux. En conséquence, la double capacité de sécréter de l'IFN-γ et de IL-2 pourrait être un avantage pour le contrôle antiviral par les cellules T CD8. Dans ce travail nous avons comparé les proportions de lymphocytes T CD8 doubles positifs (IFN-γ/IL-2) et simples positifs (IFN-γ) chez trois groupes de sujets: (i) des patients infectés par VIH-1 qui ne contrôlent pas l'infection (progresseurs), (ii) des patients infectés par VIH-1, mais contrôlant l'infection malgré l'absence de traitement ("long term non progressors" [LTNP]) et (iii) des donneurs de sang négatifs pour l'infection à VIH-1. Les résultats ont montré que les individus capables de contrôler une infection possédaient des cellules T CD8 doubles positifs (IFN-γ/IL-2), alors que les patients ne contrôlant pas l'infection procédaient prioritairement des CD8 simples positifs (IFN-γ). Spécifiquement, les lymphocytes T spécifiques pour Flu, CMV, EBV, et VII-1-1 chez les LTNP étaient tous IFN-γ/IL-2 doubles positifs. Au contraire, les lymphocytes T CD8 spécifique à VIH-1 étaient IFN-γ simples positifs chez les progresseurs. La capacité de développer une réponse IFN-γ/IL-2 pourraient être primordiale pour le contrôle de l'infection, indépendamment de la nature du virus. En effet, il a été montré que l'absence de sécrétion d'IL2 par les lymphocytes T CD8 corrélait avec leur incapacité de proliférer. Dans nos mains, cette prolifération a pu être restaurée in vitro par l'adjonction exogène d'IL-2. Toutefois, la faisabilité de ce type de complémentation in vivo n'est pas claire. Des expériences additionnelles ont permis de préciser de stade de développement des lymphocytes doubles positifs et simples positifs par le biais des marqueurs CD45RA et CCR7. Il reste maintenant à comprendre pourquoi certains lymphocytes T CD8 spécifiques sont incapables à sécréter de l'IL-2. Article 2: Le deuxième article explore des nouvelles stratégies pour induire une immunité T CD8 spécifique aux protéines du VIH-1, qui sont édités et exposés à la surface des cellules infectées. Ces signaux consistent en fragments de peptide de 8-13 acide aminés provenant de protéines virales, et exposées à la surface des cellules infectées dans le cadre des molécules spécialisées d'histocompatibilité de classe I (en anglais "major histocompatibility class I" ou MHC I). Pour mimer une infection virale, la polyprotéine Gagpolnef du VIH-1 a été insérée et exprimée dans deux vecteurs viraux atténués, soit MVA (provenant de vaccinia virus) ou NYVAC (provenant d'un poxvirus). Ensuite des souris ont été infectées avec ces virus recombinants et la réponse T CD8 aux peptides issus de Gagpolnef a été étudiée. Les souris ont été capables de développer une réponse de type CD8 T contre ces antigènes du VIH-1. Pour tester si ces antigènes pouvaient aussi être présentés par dans le cadre de molécules MHC humaines, des expériences supplémentaires ont été faites avec des souris exprimant un MHC humain. Les résultats de ces manipulations ont montré que des cellules T CD8 spécifique aux protéines du VIH pouvaient être détectées. Ce travail ouvre de nouvelles options quant à l'utilisation des virus recombinants exprimant Gagpolnef comme stratégie vaccinale contre le virus VIH-I chez l'homme. Article 3: Ces revues décrivent la réponse immunitaire à CMV ainsi que des nouvelles méthodes pouvant servir à sa détection. Une partie du manuscrit décrit la détection de cellule T à l'aide de tétramères. Il s'agit de protéines chimériques composées de 4 quatre molécules MHC liées entre elles. Elles sont ensuite "chargées" avec le peptide antigénique approprié, et utilisée pour détecter les cellules T CD8 spécifiques à ce montage. Elles sont aussi marquées par un fluorochrome, qui permet une analyse avec un cytomètre de flux, et l'isolement ultime des CD8 d'intérêt. En résumé, le travail présenté dans cette thèse indique que (i) une réponse T CD8 appropriée - définie par la présence des cellules effectrices doublement positives pour l'IFN-γ et l'IL-2 - semble indispensable pour le contrôle des infections virales, y compris par le VIH-1, (ii) une telle réponse peut être induite par des vaccin viral recombinant, et (iii) la réponse T CD8 peut être analysée et suivie grâce à plusieurs techniques, incluant celle des tétramères de MHC class I. 1.3. Résumé pour un large public Le système immunitaire humain est composé de différents éléments (cellules, tissus et organes) qui participent aux défenses de l'organisme contre les pathogènes (bactéries, virus). Parmi ces cellules, les lymphocytes T CD8, également appelés cellules tueuses, jouent un rôle important dans la réponse immunitaire et le contrôle des infections virales. Les cellules T CD8 reconnaissent de manière spécifique des fragments de protéines virales qui sont exposés à la surface des cellules infectées par le virus. Suite à cette reconnaissance, les cellules T CD8 sont capables de détruire et d'éliminer ces cellules infectées, ainsi que les virus qu'elles contiennent. Dans le contexte d'une infection par le virus de l'immunodéficience humaine (VIH), le virus responsable du SIDA, il a pu être montré que la présence des cellules T CD8 est primordiale. En effet, en l'absence de ces cellules, les individus infectés par le VIH progressent plus rapidement vers le SIDA. Au cours de la vie, l'Homme est exposé à plusieurs virus. Mais à l'opposé du VIH, certains d'entre eux ne causent pas des maladies graves : par exemple le virus de la grippe (Influenza), le cytomégalovirus ou encore le virus d'Epstein-Barr. Certains de ces virus peuvent être contrôlés et éliminés de l'organisme (p. ex. le virus de la grippe), alors que d'autres ne sont que contrôlés par notre système immunitaire et restent présents en petite quantité dans le corps sans avoir d'effet sur notre santé. Le sujet de mon travail de thèse porte sur la compréhension du mécanisme de contrôle des infections virales par le système immunitaire : pourquoi certains virus peuvent être contrôlés ou même éliminés de l'organisme alors que d'autres, et notamment le VIH, ne le sont pas. Ce travail a permis de démontrer que les cellules T CD8 spécifiques du VIH ne sécrètent pas les mêmes substances, nécessaires au développement d'une réponse antivirale efficace, que les cellules T CD8 spécifiques des virus contrôlés (le virus de la grippe, le cytomégalovirus et le virus d'Epstein-Barr). Parallèlement nous avons également observé que les lymphocytes T CD8 spécifiques du VIH ne possèdent pas la capacité de se diviser. Ils sont ainsi incapables d'être présents en quantité suffisante pour assurer un combat efficace contre le virus du SIDA. La (les) différence(s) entre les cellules T CD8 spécifiques aux virus contrôlés (grippe, cytomégalovirus et Epstein-Barr) et au VIH pourront peut-être nous amener à comprendre comment restaurer une immunité efficace contre ce dernier.

Characteristics of non-responders to self-reported questionnaires in a large inflammatory bowel disease cohort study.

BACKGROUND: A major threat to the validity of longitudinal cohort studies is non-response to follow-up, which can lead to erroneous conclusions. The objective of this study was to evaluate the profile of non-responders to self-reported questionnaires in the Swiss inflammatory bowel disease (IBD) Cohort. METHODS: We used data from adult patients enrolled between November 2006 and June 2011. Responders versus non-responders were compared according to socio-demographic, clinical and psychosocial characteristics. Odds ratio for non-response to initial patient questionnaire (IPQ) compared to 1-year follow-up questionnaire (FPQ) were calculated. RESULTS: A total of 1943 patients received IPQ, in which 331 (17%) did not respond. Factors inversely associated with non-response to IPQ were age >50 and female gender (OR = 0.37; p < 0.001 respectively OR = 0.63; p = 0.003) among Crohn's disease (CD) patients, and disease duration >16 years (OR = 0.48; p = 0.025) among patients with ulcerative colitis (UC). FPQ was sent to 1586 patients who had completed the IPQ; 263 (17%) did not respond. Risk factors of non-response to FPQ were mild depression (OR = 2.17; p = 0.003) for CD, and mild anxiety (OR = 1.83; p = 0.024) for UC. Factors inversely associated with non-response to FPQ were: age >30 years, colonic only disease location, higher education and higher IBD-related quality of life for CD, and age >50 years or having a positive social support for UC. CONCLUSIONS: Characteristics of non-responders differed between UC and CD. The risk of non-response to repetitive solicitations (longitudinal versus transversal study) seemed to decrease with age. Assessing non-respondents' characteristics is important to document potential bias in longitudinal studies.

Single centre experience of the application of self navigated 3D whole heart cardiovascular magnetic resonance for the assessment of cardiac anatomy in congenital heart disease.

BACKGROUND: For free-breathing cardiovascular magnetic resonance (CMR), the self-navigation technique recently emerged, which is expected to deliver high-quality data with a high success rate. The purpose of this study was to test the hypothesis that self-navigated 3D-CMR enables the reliable assessment of cardiovascular anatomy in patients with congenital heart disease (CHD) and to define factors that affect image quality. METHODS: CHD patients ≥2 years-old and referred for CMR for initial assessment or for a follow-up study were included to undergo a free-breathing self-navigated 3D CMR at 1.5T. Performance criteria were: correct description of cardiac segmental anatomy, overall image quality, coronary artery visibility, and reproducibility of great vessels diameter measurements. Factors associated with insufficient image quality were identified using multivariate logistic regression. RESULTS: Self-navigated CMR was performed in 105 patients (55% male, 23 ± 12y). Correct segmental description was achieved in 93% and 96% for observer 1 and 2, respectively. Diagnostic quality was obtained in 90% of examinations, and it increased to 94% if contrast-enhanced. Left anterior descending, circumflex, and right coronary arteries were visualized in 93%, 87% and 98%, respectively. Younger age, higher heart rate, lower ejection fraction, and lack of contrast medium were independently associated with reduced image quality. However, a similar rate of diagnostic image quality was obtained in children and adults. CONCLUSION: In patients with CHD, self-navigated free-breathing CMR provides high-resolution 3D visualization of the heart and great vessels with excellent robustness.

Validation of a brief form of the Perceived Neighborhood Social Cohesion questionnaire.

The aim of this study was the validation of a brief form of the Perceived Neighborhood Social Cohesion questionnaire using data from 5065 men from the "Cohort Study on Substance-Use Risk Factors." A 9-item scale covering three factors was proposed. Excellent indices of internal consistency were measured (α = .93). The confirmatory factor analyses resulted in acceptable fit indices supporting measurement invariance across French and German forms. Significant correlations were found between the brief form of the Perceived Neighborhood Social Cohesion questionnaire, and satisfaction and self-reported health, providing evidence of the concurrent validity of the scale. Perceived neighborhood social cohesion, and depression and suicide attempts were negatively associated, sustaining the protective effect of perceived social cohesion.